Survivin Down-regulation Plays a Crucial Role in 3-Hydroxy-3-methylglutaryl Coenzyme A Reductase Inhibitor-induced Apoptosis in Cancer

Abstract

3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (HRIs) are widely used to reduce serum cholesterol in patients with hypercholesterolemia. Previous studies have shown that HRIs can induce apoptosis in colon cancer cells. In this study, we investigated the mechanisms underlying the apoptosis-inducing effect of HRIs in greater detail. The HRI lovastatin induced apoptosis in the human colon cancer cell line SW480 by blocking the cholesterol synthesis pathway. Immunoblot analysis of antiapoptotic molecules, including survivin, XIAP, cIAP-1, cIAP-2, Bcl-2, and Bcl-X L , revealed that only survivin expression was decreased by lovastatin. Survivin downregulation by RNA interference induced apoptosis, and survivin overexpression rendered the cells resistant to lovastatin-induced growth inhibition. These results indicate that survivin downregulation contributes substantially to the proapoptotic properties of lovastatin. Farnesyl pyrophosphate and geranylgeranyl pyrophosphate, two downstream intermediates in the cholesterol synthesis pathway, simultaneously reversed survivin down-regulation and the blocking of Ras isoprenylation by lovastatin. Ras isoprenylation is important for the activation of Ras-mediated signaling, including the activation of the phosphatidylinositol 3-kinase (PI3-kinase)/Akt pathway. The PI3-kinase inhibitor down-regulated survivin in SW480 cells. In addition, lovastatin blocked Ras activation and Akt phosphorylation. We conclude that survivin down-regulation is crucial in lovastatin-induced apoptosis in cancer cells and that lovastatin decreases survivin expression by inhibiting Ras-mediated PI3-kinase activation via the blocking of Ras isoprenylation.3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) 3 reductase inhibitors (HRIs) are widely used to reduce serum cholesterol and are well tolerated by patients with hypercholesterolemia (1). HRIs prevent the formation of mevalonate from HMG-CoA by inhibiting the enzyme HMG-CoA reductase, thereby inhibiting cholesterol synthesis (2). In large clinical trials designed to study the changes in coronary events in coronary heart disease patients receiving HRIs, the number of newly diagnosed colon cancer cases showed a reduction of between 43% (3) and 19% (4) during a 5-year follow-up period. It has been reported that HRIs could induce apoptosis in colon cancer cells (5-7). Farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP), two downstream intermediates in the cholesterol synthesis pathway, belong to a class of compounds named isoprenoids. They are bound to several cellular proteins, including small GTPases such as Ras, Rho, and Rac, by a posttranslational modification known as isoprenylation. This process involves the addition of a 15-carbon farnesyl chain in FPP (farnesylation) or a 20-carbon geranylgeranyl chain in GGPP (geranylgeranylation) to a cysteine sulfhydryl group near the carboxyl terminus. Isoprenylation of these proteins is crucial for membrane attachment (8, 9) and the subsequent acquisition of biological activity (10)...

YM155 Reverses Statin Resistance in Renal Cancer by Reducing Expression of Survivin

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